TLRs form a family of pathogen sensors. They respond to a pathogen component, induce an activation signal, and induce a phylactic response. TLRs are not only important for phylaxis but also involved in inflammation induction in disease conditions of autoimmune diseases and the like.
Of about 10 kinds of TLRs, TLR3, TLR7, TLR8, and TLR9 are distributed in endoplasmic reticula which are intracellular organelles and recognize bacteria- or virus-derived nucleic acids. TLR7 and TLR8 recognize single-stranded RNA, while TLR9 recognizes unmethylated single-stranded DNA (CpG-DNA) containing CpG motifs.
Since different from two-stranded RNA specific to virus, single-stranded RNA or DNA does not greatly differ from a nucleic acid derived from a host, TLRs cause a response against own cells, leading to an autoimmune disease, without precise control of their ligand recognition mechanism.
In this respect, the autoimmune response by TLR7 is controlled by limiting a nucleic acid recognition site to endo lysosomes (Non-patent Document 1). In a stationary state, extracellular self-nucleic acids are degraded rapidly so that they do not reach intracellular endo lysosomes and therefore, are not recognized by TLR7. On the other hand, microorganism nucleic acids protected by cell walls of bacteria or virions reach endo lysosomes and there, they are released for the first time and recognized by TLR7.
When self-nucleic acids acquire resistance against degradation due to mutual action with an anti-microorganism peptide or autoantibody and can reach endo lysosomes, TLR7-dependent autoimmune response is caused. In fact, relation of TLR7 to psoriasis or systemic lupus erythematosus (SLE) is suggested (Non-patent Documents 2 to 4).
TLR7 is therefore thought to be a therapeutic target in TLR7-dependent autoimmune diseases such as psoriasis and SLE and various methods for suppressing expression or function of TLR7 have hitherto been proposed. More specifically, a method of using an oligo DNA having an antagonism against TLR7 or a micro RNA for suppressing expression of TLR7 has been tried. In general, however, safety of nucleic acid drugs is unknown. In addition, it cannot be denied that the complete inhibition of the function of TLR7 may cause a risk such as infectious diseases.
From the standpoint of safety and specificity, antibody drugs are desired. As described above, however, TLR7 has been thought to be present only in endo lysosomes and isolated from the cell surface for limiting an immune response, which has prevented use of antibodies acting only on the cell surface. As a result, there has been no attempt to use an antibody drug.
It is reported that similar to TLR7, TLR9 is involved in the disease condition of psoriasis (Non-patent Document 2).
TLR9 also has been thought to be a therapeutic target of autoimmune diseases such as psoriasis and SLE. Similarly, expression of it in the cell surface has been thought not to occur. As a result, there has been no attempt to use an antibody drug.